Impact of Donor Age in the Selection of a Haploidentical or a Matched-Related Donor: A Secondary Analysis of a CIBMTR Database

Introduction Hematopoietic cell transplantation (HCT) is a curative treatment for several malignant diseases¹. Unfortunately, only a minority will have the gold-standard donor, an HLA-matched sibling donor, and therefore most patients will undergo HCT with an alternative donor. Donor age has been increasingly recognized as an important prognostic factor^2,3. The objective of this study was to analyze donor age in patients undergoing haploidentical (Haplo) or matched unrelated donor (MUD) HCT, both with PTCy, and if donor age can help to decide whether to choose a Haplo or a MUD donor.

Methods We used the Center for International Blood and Marrow Transplant Research (CIBMTR) dataset publicly available whose results were published by Gooptu et al⁴. The original study compared Haplo with MUD, HLA 8/8, in which all patients received PTCy-based graft-versus-host disease (GVHD) prophylaxis. First, we compared Haplo HCT and donors ≥ 35 y/o with MUD and donors < 35 y/o. Then, the opposite: Haplo HCT and donors < 35y/o with MUD and donors ≥ 35 y/o. Uni and multivariable analyses were performed with Cox models. Model selection was based on the lowest Akaike information criterion (AIC). Throughout the manuscript, Haplo is the reference category. When included in the multivariable analyses, we reported the results of Haplo vs MUD from multivariable models; otherwise, univariable analyses. Variables tested in the multivariable analyses are those reported in table 1.

Results Patients’ characteristics, including median follow-up, are in table 1, stratified by donor age. A summary of the main results is in table 2.

Haplo, ≥ 35 y/o, (older) donor vs MUD, < 35 y/o, (younger) donor

In multivariable analysis, MUD was associated with a higher overall survival (OS) compared with Haplo recipients (HR = 0.59, p < 0.001).

The relapse rate (REL) was not different between the two groups (HR = 0.94, p = 0.64), while non-relapse mortality (NRM) was lower with MUD (HR = 0.48, p < 0.001).

In multivariable analysis, grades II-IV aGVHD remained higher in Haplo recipients (HR = 0.62, p < 0.001). MUD recipients had a lower risk of having chronic GVHD (HR = 0.78, p = 0.08).

Haplo, < 35 y/o, (younger) donor vs MUD, ≥ 35 y/o, (older) donor

There was no difference in OS between the two groups (HR = 1.08, p = 0.73 for MUD vs Haplo).

One-year REL was not different (HR = 0.96, p = 0.84 for MUD vs Haplo nor 1-year NRM (HR = 1.07, p = 0.85 for MUD vs Haplo).

Grades II-IV aGVHD (HR = 1.10, p = 0.67 for MUD vs Haplo) were different. On multivariable analysis, the risk of chronic GVHD was lower for MUD compared with Haplo, although not significantly (HR = 0.57, p = 0.06).

Discussion The results of the current analyses suggest that a MUD, < 35 y/o donor, performs better than a Haplo, ≥ 35 y/o donor, in terms of OS, NRM and acute GVHD when both groups receive PTCy-based GVHD prophylaxis. On the other hand, the results of an older MUD donor (age ≥35 y/o) appear to be equivalent to an younger Haplo donor (age < 35 y/o) when PTCy GVHD prophylaxis is used in both cases. Despite the number of older MUD donors being smaller (65 patients), all point estimates were close to 1, except for chronic GVHD, which favored the older MUD donors in absolute terms.

In conclusion, our results suggest that a young MUD should be prioritized over an older Haplo donor. However, when an older MUD and a younger Haplo donors are available, the results are comparable and prioritization should take other factors in account, like CMV, ABO match, donor weight and logistics.

Acknowledgements We used the public available CIBMTR dataset.

References 1. Appelbaum, F. R. Hematopoietic-cell transplantation at 50. N. Engl. J. Med.357, 1472-1475 (2007).

2. Guru Murthy, G. S. et al. Relapse and Disease-Free Survival in Patients With Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation Using Older Matched Sibling Donors vs Younger Matched Unrelated Donors. JAMA Oncol8, 404-411 (2022).

3. Karam, E. et al. Who Is a Better Donor for Recipients of Allogeneic Hematopoietic Cell Transplantation: A Young HLA-Mismatched Haploidentical Relative or an Older Fully HLA-Matched Sibling or Unrelated Donor? Biol Blood Marrow Transplant25, 2054-2060 (2019).

4. Gooptu, M. et al. HLA-haploidentical vs matched unrelated donor transplants with posttransplant cyclophosphamide-based prophylaxis. Blood138, 273-282 (2021).

Santos:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Pfizer: Speakers Bureau.